1. Field of the Invention
The present invention relates to a 2,4-bis(trifluoroethoxy)pyridine compound which exhibits high acyl coenzyme A cholesterol acyltransferase (ACAT) inhibitory effect upon oral administration and thus is useful for prevention or treatment of hyperlipidemia, arteriosclerosis, or similar disorders, and to intermediates which are useful for producing the compound.
2. Description of the Related Art:
Acyl coenzyme A cholesterol acyltransferase (ACAT) is an enzyme which catalyzes the synthesis of cholesterol ester from cholesterol and plays an important role in the metabolism of cholesterol and its absorption in digestive organs. Although many of conventional ACAT inhibitors serving as anti-hyperlipidemia agents or anti-arteriosclerosis agents act on ACAT in the small intestine or the liver to decrease blood cholesterol level, such agents disadvantageously have side effects such as intestinal bleeding, intestinal disorder, diarrhea, and liver disorder.
According to recent studies, regression of arteriosclerosis foci per se is expected to be achieved by preventing foam-cell formation of macrophages, which play a key role in formation of foci of arteriosclerosis. Specifically, macrophage-derived foam cells (which store cholesterol esters therein as fatty droplets) are observed in a focus of arteriosclerosis. It has been revealed that the formation of macrophage-derived foam cells is closely related to the progress of the lesion. In addition, at the arteriosclerosis lesion site, the activity of ACAT on the vascular wall has been elevated, and cholesterol ester has accumulated on the vascular wall. Thus, the activity of ACAT on the vascular wall might have a close relation to arteriosclerosis (Exp. Mol. Pathol., 44, 329–339 (1986)).
Accordingly, when an ACAT inhibitor inhibits esterification of cholesterol on vascular walls, free cholesterol will be stored in vascular wall cells. The stored free cholesterols are removed by high-density lipoprotein (HDL) from the cells to the liver (reverse transport by HDL) and then metabolized. Thus, such an ACAT inhibitor can be expected to inhibit accumulation of cholesterol esters at lesion sites of arteriosclerosis (Biochim. Biophys. Acta. 2001 15, 1530 (1): 111–122). As described above, an ACAT inhibitor which inhibits ACAT present on vascular walls has been considered to have direct anti-arteriosclerosis effect.
Previously, after extensive studies focusing on a prediction that a compound which selectively inhibits ACATs present on vascular walls and thus prevents macrophages from transforming into foam cells may serve as a preventive or therapeutic agent for arteriosclerosis while producing reduced side effects, the present inventors found that a compound represented by the following formula (A):
(wherein Ar represents an aryl group which may optionally be substituted,
represents a divalent residue of benzene, pyridine, cyclohexane, or naphthalene which may optionally be substituted, X represents NH, an oxygen atom, or a sulfur atom, Y represents a sulfur atom or the like, Z represents a single bond, l is an integer of 0 to 15, m is 2 or 3, and n is an integer of 1 to 3), a salt thereof, or a solvate of the compound or the salt selectively inhibits ACATs present in the artery wall and thus is useful as a preventive or therapeutic agent for hyperlipidemia or arteriosclerosis (International Patent Publication WO98/54153).
Among the compounds described in International Patent Publication WO98/54153, a compound represented by formula (B):
and a salt thereof was found to have high solubility to water and high ACAT inhibitory effect and exhibit unique pharmacological effect in a variety of animal models. Although compound (B) and other compounds disclosed in International Patent Publication WO98/54153 exhibit excellent pharmacological effect attributed to ACAT inhibitory effect in animals, experiments performed in vitro using human liver microsomes revealed that these compounds are rapidly metabolized and thus only small percentage of unchanged compounds remains in human liver microsome. Therefore, low blood concentration of these compounds has become of concern. Moreover, on the basis of a recent knowledge that, from the mechanism of drug interaction, a drug having higher safety is produced from compounds having higher metabolic resistance, a compound having higher metabolic resistance in human liver microsome is desired.
However, it has been considered very difficult to improve stability, against metabolism, of compound (B) while maintaining its ACAT inhibitory effect, since compound (B) has many functional groups which are generally readily metabolized in living organisms, and these functional groups are believed to be essential for production of the pharmacological effect.